Synthesis and characterization of new low‐molecular‐weight lysine‐conjugated Gd‐DTPA contrast agents

Various blood pool contrast agents (CAs), characterized by intravascular distribution, have been developed to assist contrast enhanced magnetic resonance angiography (MRA). Among these CAs, the DTPA derivatives conjugated to synthetic polypeptides, such as polylysine, represent attractive candidates for blood pool imaging. However, due to the presence of charged residues located on their backbone, these agents are retained in the kidneys and this compromises their long blood half‐life. In order to overcome this major drawback of the polylysine compounds, two new low‐molecular‐weight CAs were synthesized in the present work by conjugating four or six 1‐p‐isothiocyanatobenzyl‐DTPA moieties to tri‐ or penta‐Lys peptides (Gd‐DTPA)₄Lys₃ and (Gd‐DTPA)₆Lys₅], respectively. All the –NH₂ groups of Lys were thus blocked by covalent conjugation to DTPA. The stability and relaxometric properties of these compounds, as well as their pharmacokinetic and biodistribution characteristics, were then evaluated. The half‐life in blood of these new polylysine derivatives, as determined in rats, is twofold longer than that of Gd‐DTPA. The compounds could thus be optimal blood pool markers for MRA, which typically uses fast acquisition times. The absence of positive molecular charge did not limit their retention in kidneys 2 h after administration. On the other hand, (Gd‐DTPA)₄Lys₃ is retained in kidneys to a lesser extent than (Gd‐DTPA)₆Lys₅. Their moderate retention in blood and their higher stability and relaxivity in comparison with Gd‐DTPA highlight these polylysine derivatives as optimal compared with previously developed polylysine compounds. Copyright © 2010 John Wiley & Sons, Ltd.